Application of constrained optimization methods in health services research: Report 2 of the ISPOR Optimization Methods Emerging Good Practices Task Force

Background Constrained optimization methods are already widely used in health care to solve problems that represent traditional applications of operations research methods, such as choosing the optimal location for new facilities or making the most efficient use of operating room capacity. Objectives In this paper we illustrate the potential utility of these methods for finding optimal solutions to problems in health care delivery and policy. To do so, we selected three award-winning papers in health care delivery or policy development, reflecting a range of optimization algorithms. Two of the three papers are reviewed using the ISPOR Constrained Optimization Good Practice Checklist, adapted from the framework presented in the initial Optimization Task Force Report. The first case study illustrates application of linear programming to determine the optimal mix of screening and vaccination strategies for the prevention of cervical cancer. The second case illustrates application of the Markov Decision Process to find the optimal strategy for treating type 2 diabetes patients for hypercholesterolemia using statins. The third paper (described in Appendix 1) is used as an educational tool. The goal is to describe the characteristics of a radiation therapy optimization problem and then invite the reader to formulate the mathematical model for solving it. This example is particularly interesting because it lends itself to a range of possible models, including linear, nonlinear, and mixed-integer programming formulations. From the case studies presented, we hope the reader will develop an appreciation for the wide range of problem types that can be addressed with constrained optimization methods, as well as the variety of methods available. Conclusions Constrained optimization methods are informative in providing insights to decision makers about optimal target solutions and the magnitude of the loss of benefit or increased costs associated with the ultimate clinical decision or policy choice. Failing to identify a mathematically superior or optimal solution represents a missed opportunity to improve economic efficiency in the delivery of care and clinical outcomes for patients. The ISPOR Optimization Methods Emerging Good Practices Task Force’s first report provided an introduction to constrained optimization methods to solve important clinical and health policy problems. This report also outlined the relationship of constrained optimization methods relative to traditional health economic modeling, graphically illustrated a simple formulation, and identified some of the major variants of constrained optimization models, such as linear programming, dynamic programming, integer programming, and stochastic programming. The second report illustrates the application of constrained optimization methods in health care decision making using three case studies. The studies focus on determining optimal screening and vaccination strategies for cervical cancer, optimal statin start times for diabetes, and an educational case to invite the reader to formulate radiation therapy optimization problems. These illustrate a wide range of problem types that can be addressed with constrained optimization methods

The complications of ‘hiring a hubby’: gender relations and the commoditisation of home maintenance in New Zealand

This paper examines the commoditization of traditionally male domestic tasks through interviews with handymen who own franchises in the company ‘Hire a Hubby’ in New Zealand and homeowners who have paid for home repair tasks to be done. Discussions of the commoditization of traditionally female tasks in the home have revealed the emotional conflicts of paying others to care as well as the exploitative and degrading conditions that often arise when work takes place behind closed doors. By examining the working conditions and relationships involved when traditionally male tasks are paid for, this paper raises important questions about the valuing of reproductive labour and the production of gendered identities. The paper argues that while working conditions and rates of pay for ‘hubbies’ are better than those for people undertaking commoditized forms of traditionally female domestic labour, the negotiation of this work is still complex and implicated in gendered relations and identities. Working on the home was described by interviewees as an expression of care for family and a performance of the ‘right’ way to be a ‘Kiwi bloke’ and a father. Paying others to do this labour can imply a failure in a duty of care and in the performance of masculinity

The cost-effectiveness of sequences of biological disease-modifying antirheumatic drug treatment in England for patients with rheumatoid arthritis who can tolerate methotrexate.

Objective: To ascertain whether strategies of treatment with a biological diseasemodifying antirheumatic drug (bDMARD) were cost-effective in an English setting. Results are presented for those patients with moderate-to-severe rheumatoid arthritis (RA) and those with severe RA. Methods: An economic model to assess the cost-effectiveness of seven bDMARDs was developed. A systematic literature review and network meta-analysis was undertaken to establish relative clinical effectiveness. The results together with estimates of: Health Assessment Questionnaire (HAQ) score following European League Against Rheumatism response; annual costs, and utility, per HAQ band; trajectory of HAQ for patients on bDMARDs; and trajectory of HAQ for patients on non-biologic therapy (NBT) were used to populate the model. Results were presented as those associated with the strategy with the median cost-effectiveness. Supplementary analyses were undertaken assessing the change in cost-effectiveness where only patients with the most severe prognoses on NBT were provided with bDMARD treatment. The cost per QALY values were compared with reported thresholds from the National Institute for Health and Care Excellence of £20,000 to £30,000. Results: In the primary analyses, the cost per QALY of a bDMARD strategy was £41,600 for patients with severe RA and £51,100 for those with moderate-to-severe RA. Under the supplementary analyses the cost per QALY fell to £25,300 for those with severe RA and to £28,500 for those with moderate-to-severe RA. Conclusion: The cost-effectiveness of bDMARDs in RA in England is questionable and only meets current accepted levels in subsets of patients with the worst prognoses

A binding kinetics study of human adenosine A(3) receptor agonists

The human adenosine A(3) (hA(3)) receptor has been suggested as a viable drug target in inflammatory diseases and in cancer. So far, a number of selective hA(3) receptor agonists (e.g. IB-MECA and 2-CI-IB-MECA) inducing anti-inflammatory or anticancer effects are under clinical investigation. Drug-target binding kinetics is increasingly recognized as another pharmacological parameter, next to affinity, for compound triage in the early phases of drug discovery. However, such a kinetics-driven analysis has not yet been performed for the hA3 receptor. In this study, we first validated a competition association assay for adenosine A3 receptor agonists to determine the target interaction kinetics. Affinities and Kinetic Rate Index (KRI) values of 11 ribofurano and 10 methanocarba nucleosides were determined in radioligand binding assays. Afterwards, 15 analogues were further selected (KRI 1.35) for full kinetics characterization. The structure-kinetics relationships (SKR) were derived and longer residence times were associated with methanocarba and enlarged adenine N-6 and C2 substitutions. In addition, from a k(on)-k(off)K(D) kinetic map we divided the agonists into three subgroups. A residence time "cliff' was observed, which might be relevant to (N)-methanocarba derivatives' rigid C2-arylalkynyl substitutions. Our findings provide substantial evidence that, next to affinity, additional knowledge of binding kinetics is useful for developing and selecting new hA(3)R agonists in the early phase of the drug discovery process.Medicinal Chemistr